ABSTRACT
RATIONALE: Accumulating evidence indicates that schizophrenia and autism spectrum disorder patients are marked by cognitive deficits in working memory and strategy switching. There is accumulating evidence that 5-hydroxytryptamine (5-HT)(6) receptors may serve as a useful target to improve cognitive functioning. OBJECTIVES: In the present experiments, the novel 5-HT(6) antagonist, PRX-07034, was examined for its selectivity of the 5-HT(6) receptor, as well as its effect on delayed spontaneous alternation and strategy switching. METHODS: The binding affinity of PRX-07034 to the 5-HT(6) receptor, other 5-HT receptors, as well as other G-protein coupled receptors, ion channels, and transporters was evaluated. Cyclic AMP production was measured from transfected HEK-293 cells. In separate behavioral experiments, rats received different doses of PRX-07034 (0.1, 1, or 3 mg/kg, i.p.) 30 min prior to delayed spontaneous alternation testing or prior to the acquisition and switch phases in a place-response switch test. RESULTS: The results indicated that PRX-07034 is both a potent (Ki = 4-8 nM) and highly selective 5-HT(6) receptor antagonist (≥100-fold selectivity for the 5-HT(6) receptor compared to 68 other GPCRs, ion channels, and transporters, except D(3) (Ki = 71 nM) and 5-HT(1B) (Ki = 260 nM) receptors. For cyclic AMP quantification, PRX-07034 demonstrated antagonist activity (IC(50) = 19 nM) without an effect on basal levels and did not show any agonist activity up to 10 µM. PRX-07034 at 1 and 3 mg/kg (but not 0.1 mg/kg) significantly enhanced delayed spontaneous alternation. The drug at 1 and 3 mg/kg also enhanced switching between a place and response strategy, but did not affect initial learning of either a place or response discrimination. CONCLUSIONS: These findings demonstrate that PRX-07034 is a selective 5-HT(6) receptor antagonist that may represent a novel treatment for enhancing working memory and cognitive flexibility.
Subject(s)
Cognition/drug effects , Memory, Short-Term/drug effects , Receptors, Serotonin/metabolism , Serotonin Antagonists/pharmacology , Animals , Cognition/physiology , HEK293 Cells , Humans , Male , Memory, Short-Term/physiology , Protein Binding/drug effects , Random Allocation , Rats , Rats, Long-Evans , Reaction Time/drug effects , Reaction Time/physiologyABSTRACT
To address the development of early anxiety disorders across the lifespan, the High USV line of rats was bred based on rates of infant ultrasonic vocalization in the 40-50 kHz range of predominant frequencies (USV) to maternal separation at postnatal day (P) 10. In this study, rates of USV in High line infants (pups: Postnatal Day 11+/-1) were compared to those of randomly-bred controls in response to EPIX compound PRX-00023, a unique serotonin (5-HT) agonist, acting exclusively at the 5-HT1A receptor, or buspirone, a nonspecific 5HT1A agonist. After testing, pups were examined for sedation and other drug-related effects. The results indicated that all doses of buspirone reduced USV rates in isolation, consistent with other reports. PRX-00023 significantly reduced USV rates at the lowest doses (0.01-0.05 mg/kg). None of the PRX-00023 doses produced sedation, whereas all but the lowest dose of buspirone (0.1 mg/kg) produced sedation effects. The results suggest that this compound alleviates infantile anxiety-like behavior with great specificity in rats bred for high anxiety/depressive phenotypes by selectively targeting 5-HT1A receptors, possibly by both pre- and post-synaptic mechanisms.